Sporadic Insulinoma Presenting as Early Morning Night TerrorsAAP NewsAdditional investigation revealed a sporadic insulinoma as the etiology of his hypoglycemia and all symptoms were resolved after pancreaticoduodenectomy. The importance of obtaining critical laboratory samples is highlighted and appropriate radiologic, ...

Abstract
Objective To investigate the effect of thioredoxin interacting protein (TXNIP) over-expression on the apoptosis of MIN6 β-cells and the mechanism involved. Methods Lentivirus carrying TXNIP gene was used to infect MIN6 β-cells in logarithmic growth phase, and the infection efficiency was evaluated by fluorescence microscope and Western blotting. Then MIN6 β-cells were divided into three groups: control group, empty lentivirus vector (LV-GFP) group and TXNIP over-expression (LV-GFP-TXNIP) group. CCK-8 assay was used to detect cell proliferation. AnnexinV-FITC/PI double staining was utilized to measure the apoptosis of MIN6 cells. Western blotting was applied to detect the expressions of TXNIP protein, TRX, Bax, Bcl2, cleaved caspase-3 (c-caspase-3), p38 mitogen-activated protein kinase (p38MAPK), phospho-p38MAPK (p-p38MAPK) proteins in the MIN6 β-cells before and after treated with p38MAPK inhibitor SP169316. Results At 72 hours after the infection, the infection rate reached (87.10±2.30)% and (92.21±0.54)% in LV-GFP group and LV-GFP-TXNIP group, respectively, suggesting that lentivirus-mediated TXNIP over-expression was desirable. Compared with control group and LV-GFP group, the cell viability markedly decreased, and cell apoptosis, Bax/Bcl2 ratio, expression of c-caspased-3 and p38MAPK phosphorylation significantly increased in LV-GFP-TXNIP group. However, both the Bax/Bcl2 ratio and c-caspase-3 protein expression in LV-GFP-TXNIP group were obviously reduced after treated with p38MAPK inhibitor. Conclusion TXNIP over-expression might promote the apoptosis of MIN6 cells via activating the p38 MAPK pathway.

Abstract
Recurrent hypoglycemia is common, but its presentation is often insidious resulting in delays in diagnosis and significant morbidity. We describe a case of an insulinoma presenting with falls and confusion in a patient with tuberous sclerosis, demonstrating the importance of early hypoglycemia identification and a potential shared molecular pathogenesis.

[Severe hypoglycaemia due to insulinoma after gastric bypass surgery].

Ugeskr Laeger. 2018 Apr 23;180(17):

Authors: Sjøbjerg A, Poulsen PL, Kramer S, Richelsen B

Abstract
Postprandial hypoglycaemia with endogenous hyper-insulinaemia is relatively common after gastric bypass (GB) surgery. However, alternative aetiologies of hypoglycaemia should be kept in mind. We report a case of severe hypo-glycaemia in a patient who had previously undergone GB surgery for morbid obesity. Hypoglycaemic episodes differed from typical GB-related hypoglycaemia by occurring during fasting periods. Examination revealed insulinoma, and nine months after resection the patient remained symptom free.

Abstract
Resveratrol (RSV) has been reported to exert anti-inflammatory, anti-oxidant and anti-cancer effects both in vivo and in vitro, and is widely used to treat various diseases. However, the effect of RSV on type 2 diabetes (T2D) is still unclear. The present study aimed to explore the effect of RSV on UA-induced cell injury and dysfunction in pancreatic β-cells. The mouse insulinoma cell line Min6 was treated with 5 mg/dl UA and different concentrations of RSV. Then, cell viability, apoptosis, apoptosis-associated factors, iNOS expression and insulin secretion were examined by CCK-8, flow cytometry, western blot, qRT-PCR and glucose-stimulated insulin secretion (GSIS), respectively. MiR-126 inhibitor and sh-KLF2 were transfected into Min6 cells to alter the expression levels and to reveal the regulatory relationship with RSV. PI3K/AKT signal pathway was analyzed by western blot to uncover the underling mechanism. UA treatment suppressed cell viability, promoted apoptosis, enhanced iNOS expression and decreased insulin secretion in Min6 cells. RSV significantly alleviated UA-induced injury and dysfunction in Min6 cells. The expression level of miR-126 was up-regulated by RSV, and suppression of miR-126 abolished the protective effect of RSV on UA-injured Min6 cells. Additionally, RSV up-regulated KLF2 expression, the promoting effect of RSV on miR-126 expression was reversed by KLF2 silence. Besides, RSV activated PI3K/AKT signal pathway by up-regulation of miR-126 in UA-injured Min6 cells. These data indicated that RSV could protect Min6 cells against UA-induced injury and dysfunction by regulation of miR-126 and activation of PI3K/AKT signal pathway.

Abstract
BACKGROUND: Benign insulinoma is the most common functioning neuroendocrine tumor of the pancreas, and its incidence is estimated at 0.4%. The treatment of choice is organ-preserving resection. The aim of this study was to compare short-term and long-term outcomes of minimally invasive laparoscopic or robotic enucleation (MIC-EN) and open enucleation (O-EN) for sporadic benign insulinoma.
METHODS: A retrospective bi-institutional analysis of 71 patients who underwent an enucleation for sporadic benign insulinoma between 2003 and 2016 was performed. Patients were analyzed according to intention-to-treat principle.
RESULTS: Fifteen (21%) patients underwent MIC-EN (three robotic and 12 laparoscopic) and 56 (79%) patients O-EN. In all MIC-EN patients, the insulinoma was localized by preoperative imaging compared to only 62.5% (35 of 56) patients in the O-EN group (p = 0.005). Three of the MIC-EN patients (20%) with insulinomas in the pancreatic head had to undergo a conversion. Excluding conversions, MIC-EN procedures were shorter (145 vs 180, p = 0.036) compared to O-EN surgery. Late complications and pathological data did not differ between groups, excluding margin status R1 MIC-EN (26.7%) compared to O-EN (10.7%, p = 0.115). After a median follow-up of 75 (range 1-151) months, all patients were alive, but four (5.6%) patients (one after MIC-EN and three after O-EN) developed a functional recurrence. No patient with a R1 resection had a disease recurrence.
CONCLUSIONS: MIC-EN for benign sporadic insulinoma is a safe procedure with at least similar short-term and long-term postoperative outcomes as the open technique. Thus, preoperatively localized benign insulinoma should be approached laparoscopically, if technically feasible.

Abstract
Pancreatic β-cell Tcf7l2 deletion or its functional knockdown suggested the essential role of this Wnt pathway effector in controlling insulin secretion, glucose homeostasis, and β-cell gene expression. As the LIM homeodomain protein Isl1 is a suggested Wnt pathway downstream target, we hypothesize that it mediates metabolic functions of Tcf7l2. We aimed to determine the role of Isl1 in mediating the function of Tcf7l2 and the incretin hormone GLP-1 in pancreatic β-cells. Effect of dominant negative TCF7L2 (TCF7L2DN) mediated Wnt pathway functional knockdown on Isl1 expression was determined in βTCFDN mouse islets and in the rat insulinoma cell line INS-1 832/13. Luciferase reporter assay and chromatin immunoprecipitation were utilized to determine whether Isl1 is a direct downstream target of Tcf7l2. TCF7L2DN adenovirus infection and siRNA-mediated Isl1 knockdown on β-cell gene expression were compared. Furthermore, Isl1 knockdown on GLP-1 stimulated β-catenin S675 phosphorylation and insulin secretion was determined. We found that TCF7L2DN repressed Isl1 levels in βTCFDN islets and the INS-1 832/13 cell line. Wnt stimulators enhanced Isl1 promoter activity and binding of Tcf7l2 on Isl1 promoter. TCF7L2DN adenovirus infection and Isl1 knockdown generated similar repression on expression of β-cell genes, including the ones that encode GLUT2 and GLP-1 receptor. Either TCF7L2DN adenovirus infection or Isl1 knockdown attenuated GLP-1-stimulated β-catenin S675 phosphorylation in INS-1 832/13 cells or mouse islets and GLP-1 stimulated insulin secretion in INS-1 832/13 or MIN6 cells. Our observations support the existence of Tcf7l2-Isl1 transcriptional network and we suggest that this network also mediates β-cell function of GLP-1.

Abstract
We investigated the prevalence of glutamic acid decarboxylase 65 autoantibody (GADA), insulinoma-associated protein 2 autoantibody (IA2A), and insulin autoantibody (IAA) in 750 children with type 1 diabetes (T1D) living in Taiwan. GADA, IA2A, and IAA were measured by radioimmunoassay. The data were assessed by χ2 test, binary logistic regression, and Spearman rank correlation. Of the 750 T1D patients, 66.3% had GADA, 65.3% IA2A, 35.7% IAA, and 17.2% no autoantibodies. The prevalence of GADA and IA2A significantly decreased along T1D duration. The positivity of either GADA or IA2A was 89.4% within the first year of disease and decreased to 36.7% after 9 years (P = 1.22 × 10-20). Female patients had significantly higher prevalence of GADA compared with male patients (72.3% vs. 59.7%, P = 0.00027). The patients diagnosed before 12 years of age had a positive rate of 92.2% for either GADA or IA2A. Patients diagnosed at age 12 or above had a significantly lower positive rate of 81.6% (P = 0.011). GADA and IA2A significantly correlated with each other (rs = 0.245, P = 1.09 × 10-11). We concluded that autoantibodies were detectable in 89.4% of T1D patients within one year after diagnosis. Their prevalence declined with disease duration. GADA was more prevalent in female patients. GADA and IA2A weakly correlated with each other.

Abstract
Here, we report the diagnosis and treatment of a very rare case of malignant insulinoma derived from ectopic pancreas. A middle-aged woman presented with a 6-year history of recurrent hypoglycemia with multiple lesions in liver. Admission workup revealed elevated serum insulin and C-peptide, as well as multiple lesions in the liver (largest being 4.3 cm), enlarged lymph nodes around the pancreas, and a lesion (of 3.5 cm) at the proximal jejunum, as shown by contrast computed tomography (CT). Liver biopsy showed the lesions to be well-differentiated neuroendocrine tumors, grade G1. 68Gallium-exendin-4 positron emission tomography/CT confirmed the origin as the lesion located at the jejunum. The combination treatment of everolimus plus long-acting octreotide relieved symptoms and achieved a partial tumor response. Maintenance treatment of the somatostatin analog (ie, octreotide) alone was administered. Three years of follow-up, up to the writing of this report, showed good survival, with the patient remaining asymptomatic and euglycemic without disease progression. This case shows that 68Gallium-exendin-4 positron emission tomography/CT is useful for locating insulinoma, especially for insulinoma derived from ectopic pancreas, and that everolimus plus octreotide with maintenance somatostatin analog alone is an effective drug strategy for treating inoperable malignant insulinoma.

Abstract
A middle-aged male patient with recurrent hypoglycemia was diagnosed as insulinoma according to the symptoms and the laboratory tests. Laboratory tests also showed low cortisol and adrenocortico-tropic hormone (ACTH) levels, therefore adrenal insufficiency was diagnosed and hydrocortisone was given. The hormone replacement therapy was terminated after surgery, and ACTH and cortisol levels returned to normal.

The role of minimally invasive surgery in neuroendocrine pancreatic tumors.

Minerva Chir. 2017 Jun;72(3):237-247

Authors: Yiannakopoulou E

Abstract
Minimally invasive surgery has an established role in the treatment of patients with pancreatic neuroendocrine tumors (pNETs). Enucleation is an established treatment option for insulinomas. The necessity of organ sparing surgery is well established in the case of multiple pNETs. A number of studies have demonstrated the efficacy and safety of laparoscopic surgery for the treatment of pNETs. However, pNETs are rare, and large studies focusing on pNET patients are difficult to be designed unless multicenter experience is collected. Authors investigating the role of minimally invasive pancreatic surgery should be encouraged to report separately the results that involve patients presenting with pNETs. A European registry of patients with pNETs treated with minimally invasive surgery would allow further investigation of the optimal treatment of these patients. Especially in the case of syndromic pNETs, that are rare entities, co-operation and exchange of information is needed among different centers for sharing experience and transferring knowledge. Existing data come from small cohort studies, case series and case reports. Given that, pancreatic surgery is especially demanding advanced surgery with training that is not yet standardized, further research is needed for defining its role in the treatment of pancreatic neuroendocrine tumors. Regarding the role of robot-assisted surgery in the treatment of pNETS, data are quite scarce.

Abstract
Small (<2 cm) sporadic neuroendocrine pancreatic neoplasms (pNENs) are a heterogeneous group of neoplasms, which can be separated into functionally active or non-functional tumors. Functionally active pNENs release various hormones, such as insulin, gastrin, glucagon and vasoactive intestinal hormones and therefore lead to severe symptoms independent of their size. The main symptoms include hypoglycemia, coma (insulinoma), diarrhea (gastrinoma, VIPoma), intestinal ulcers (gastrinoma) and hyperglycemia (glucagonoma). Asymptomatic inactive pNENs do not cause a hormonal syndrome even though in immunohistochemistry they are positive for various hormones and endocrine markers (e.g. chromogranin and synaptophysin). Non-active small pNENs are increasingly being found because of the widespread use of high-resolution imaging and are named incidental pNENs. The current therapy algorithms of small functionally active and non-functional pNENs are very different and include besides non-operative management and surveillance (wait and see strategy) of non-active pNENs (G1, low G2), all minimally invasive, open and robotic techniques of pancreas resection. Until today almost all recommendations of surgical and nonsurgical therapy algorithms have been established based on retrospective data.

Abstract
Despite growing evidence for GLP-1R molecular-based imaging, successful localization of insulinomas may require the use of multiple imaging modalities. Not all benign insulinomas express the GLP-1R as expected. Our case demonstrates that there is a still an important role for traditional methods for the anatomical localization of an insulinoma.

Abstract
Pancreatic neuroendocrine tumors (pNETs) constitute a heterogenous group of malignancies with varying clinical presentation, tumor biology and prognosis. The incidence of pNETs has steadily increased during the last decades with an estimated incidence 2012 of 4.8/100,000. Recent whole genome sequencing of pNETs has demonstrated mutations in the DNA repair genes MUTYH and point mutations and gene fusions in four main pathways from chromatin remodeling, DNA damage repair, activation of mechanistic target of rapamycin (mTOR) signaling and the telomere maintenance. This new information will be the foundation for new therapies in the near future for malignant pNETs. The functioning pNETs constitute about 30-40% of all pNETs displaying nine different clinical syndromes: insulinoma, Zollinger-Ellison, Verner-Morrison, glucagonoma, somatostatinomas, ectopic adrenocorticotropic hormone (ACTH) and parathyroid hormone related peptide (PTH-rP) syndromes. Single patients might also present carcinoid syndrome. The diagnostic work-up include histopathology with the new WHO 2017 Classification, biomarkers (CgA, NSE), radiology and molecular imaging including CT-scan, magnetic resonance imaging (MRI), ultrasound and PET-scan. A cornerstone in the treatment of pNETs is surgery which is rarely curative but can reduce the clinical symptoms by debulking which also include radiofrequency ablation, embolization of liver metastases. Medical treatment includes chemotherapy and the targeted agents such as everolimus, sunitinib and peptide receptor radiotherapy (PRRT). Somatostatin analogs has for the last decades been the main stay for management for clinical symptoms related to functioning pNETs and is often combined with new targeted agents as well as chemotherapy. Long-term management of functioning pNETs need a combination of different procedures, surgery, local ablation, targeted agents and somatostatin analogs. Future therapies might be based on the recent advances in molecular genetics and tumor biology.

Abstract
The proliferation of pancreatic β cells is enhanced to enable an increase in β-cell mass and to compensate for insulin resistance during pregnancy. To elucidate the mechanisms involved, we previously investigated islets from pregnant and nonpregnant mice by gene expression profiling and found that the expression of postsynaptic density-95/Discs large/zonula occludens-1 (PDZ)-binding kinase (Pbk), a member of the mitogen-activated protein kinase kinase family, is increased in pregnant mouse islets compared with control mouse islets. Among the pregnancy hormones, treatment with estradiol upregulated Pbk expression. Inhibition of Pbk expression using a small interfering RNA for Pbk reduced bromodeoxyuridine incorporation in mouse insulinoma 6 cells, which was accompanied by a decreased expression of Ccnb1, a regulatory gene involved in mitosis. Ccnb1 expression was augmented in mouse islets during pregnancy. The forced expression of Pbk using an adenovirus system in isolated mouse islets increased Ccnb1 expression, and the Pbk inhibitor HI-TOPK-032 suppressed Ccnb1 expression in islets isolated from pregnant mice. Our results suggest that Pbk contributes to the expansion of islets during pregnancy and that Ccnb1 may assist Pbk in its role in β-cell proliferation.

Abstract
INTRODUCTION: Surgical diseases of the pancreas in children are not common and may be associated with significant morbidity and potential mortality. A multidisciplinary approach is essential for correct diagnosis, surgical strategy and postoperative as well as follow-up care.
METHOD: Retrospective analysis of patients operated on due to a pathological lesion of the pancreas focused on diagnostics, operating procedures, postoperative complications, and long-term results. Between 1991 and 2016, eighty-nine children were treated in our department for a pathologic lesion of the pancreas. 39 of them were boys and 50 were girls.
RESULTS: Mean age of the patients was 9.3 years (1 month-18.4 years). Patients were followed from the operation to the age of 19, after which they were referred for follow-up to adult specialists. The indications for surgery were trauma in 34 children, solid pseudopapillary tumor in 23 children, biopsy in 10, hyperinsulinism in 8, chronic pancreatitis in 4, pancreatic cyst in 3, insulinoma in 3, carcinoma in 2, and serous cystadenoma and pancreas divisum in one patient. The most frequent procedures performed on the pancreas were distal pancreatectomy in 35 cases, the duodenum-preserving pancreatic head resection in 23 cases, pseudocystogastroanastomosis in 11 cases, 9095% pancreatic resection in 5 cases, Whipple operation in two cases, Puestow procedure in one case, tumor enucleation in one case, and tumor biopsy for cancer in one case. In 5 patients after major pancreatic injury, ERCP and papillotomy with insertion of a stent into the pancreatic duct was performed. 3 patients died, one after a polytrauma with severe pancreatic injury and two patients with pancreatic cancer.
CONCLUSION: Pancreatic surgery in children is not a common operation, and individual as well as institutional experience remains limited. After more than 20 years of experience with pancreatic surgery, we believe that close cooperation with surgeons, pediatric gastroenterologists, radiologists, anesthesiologists, intensivist, pathologists and ERCP specialists is necessary for successful diagnosis and treatment of pancreatic disease in children.Key words: pancreas pancreatic surgery in children duodenum preserving head resection of the pancreas.

Abstract
We report a case of a 58-year-old male presenting with confusion and hypoglycaemia. There had been no prior exposure to oral hypoglycaemic agents or insulin. He was found to have inappropriate endogenous hyperinsulinaemia. Insulinoma was excluded by detailed endocrine assessment. Insulin antibodies were positive in keeping with a diagnosis of insulin autoimmune syndrome (IAS). He was treated with prednisolone 5mg once daily and nutritional supplements leading to resolution of acute confusion and hypoglycaemic episodes. The patient also had severe psoriasis and following discharge was treated with a variety of immunosuppressant therapies. This was associated with disappearance of insulin antibodies after twelve months of follow up. While it is possible that there was spontaneous resolution of insulin antibodies, we speculate that his prednisolone and immunosuppressant therapy may have suppressed insulin antibody production. There are several well recognised associations with IAS and autoimmune conditions, including Grave's disease, systemic lupus erythematous and rheumatoid arthritis. To our knowledge this is the first reported case of insulin autoimmune syndrome, resolving with immunosuppressant treatment of psoriasis.

Abstract
Endoplasmic reticulum (ER), a dynamic organelle, plays an essential role in organizing the signaling pathways involved in cellular adaptation, resilience, and survival. Impairment in the functions of ER occurs in a variety of nutritive disorders including obesity and type 2 diabetes. Here, we hypothesize that (scopoletin) SPL, a coumarin, has the potential to alleviate ER stress induced in vitro and in vivo models by lipotoxicity. To test this hypothesis, the ability of SPL to restore the levels of proteins of ER stress was analyzed. Rat insulinoma 5f (RIN5f) cells and Sprague Dawley rats were the models used for this study. Groups of control and high-fat, high-fructose diet (HFFD)-fed rats were treated with either SPL or 4-phenylbutyric acid. Status of ER stress was enumerated by quantitative RT-PCR, Western blot, electron microscopic, and immunohistochemical studies. Proximal proteins of ER stress inositol requiring enzyme 1 (IRE1), protein kinase like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) were reduced in the β-cells by SPL. The subsequent signaling proteins X-box binding protein 1, eukaryotic initiation factor2α, activating transcription factor 4, and C/EBP homologous protein were also suppressed in their expression levels when treated with SPL. IRE1, PERK signaling leads to c-Jun-N-terminal kinases phosphorylation, a kinase that interrupts insulin signaling, which was also reverted upon scopoletin treatment. Finally, we confirm that SPL has the ability to suppress the stress proteins and limit pancreatic ER stress which might help in delaying the progression of insulin resistance.

Abstract
Type 1 diabetes is caused by destruction of the pancreatic β‑cells and, to date, no cure has been developed. Promoting the survival of pancreatic β‑cells may be beneficial for patients with type 1 diabetes. Puerarin is an estrogen analogue that been demonstrated in previous studies to be able to decreased blood glucose in patients with type 1 diabetes. Similar results were demonstrated in previous studies which additionally demonstrated that puerarin was able to decreased blood glucose in type 1 diabetic mice by protecting pancreatic β‑cells. However, the mechanism underlying the function of puerarin in pancreatic β‑cells remains unclear. Therefore, the present study sought to investigate the detailed function of puerarin in pancreatic β‑cells. In the present study, H2O2 was used to induce apoptosis. It was observed that puerarin significantly decreased H2O2‑induced apoptosis in mouse insulinoma MIN6 cells. It was additionally observed that puerarin decreased the levels of intracellular reactive oxygen species and mitochondrial superoxide in MIN6 cells. The protective effect of puerarin was markedly decreased by 6‑aminonicotinamide, an inhibitor of glucose‑6‑phosphate dehydrogenase (G6PD). In conclusion, the results of the present study suggested that puerarin may increase the activity of G6PD, decreased the level of oxidative stress in MIN6 cells, protect mitochondria and promote MIN6 cell survival. Investigating the mechanism underlying the effect of puerarin in MIN6 cells may provide a novel approach for development of a cure for type 1 diabetes.

Abstract
Damage to pancreatic β‑cells is closely associated with diabetes. However, the mechanism underlying injury to pancreatic β‑cells remains unclear, although hypoxia is considered as one of the leading causes. Appoptosin is a mitochondrial protein that promotes neuronal apoptosis. Studies conducted on appoptosin thus far have primarily focused on Alzheimer's disease, and have demonstrated that the expression of appoptosin is significantly increased in ischemic‑reperfused rat brains, which indicates its close association with hypoxia. However, the role of appoptosin in pancreatic β‑cells, which are sensitive to hypoxia, remains unknown. Therefore, the current study aimed to investigate the function of appoptosin in pancreatic β‑cells in a hypoxic environment. Cobalt chloride (CoCl2) was used to mimic the hypoxic status of the cells. The results of a terminal deoxynucleotidyl transferase dUTP nick‑end labeling assay demonstrated that CoCl2 promoted apoptosis in MIN6 mouse insulinoma cells, and western blotting and reverse transcription‑quantitative polymerase chain reaction results demonstrated that the activation of appoptosin was induced, promoting mitochondrial damage and caspase 3 activation. Silencing of appoptosin using short hairpin RNA significantly reduced CoCl2‑induced apoptosis in MIN6 cells. In conclusion, CoCl2 increased the expression of appoptosin, which aggravated mitochondrial damage in MIN6 cells. Therefore, inhibiting the expression of appoptosin may benefit pancreatic β-cells survival during islet transplantation.

Abstract
INTRODUCTION: Encapsulation of pancreatic islets or beta cells is a promising strategy for treatment of type 1 diabetes by providing an immune isolated environment and allowing for transplantation in a different location than the liver. However, islets used for encapsulation often show lower functionality due to the damaging of islet endothelial cells during the isolation procedure. Factors produced by endothelial cells have great impact on beta cell insulin secretion. Therefore, mutual signaling between endothelial cells and beta cells should be considered for the development of encapsulation systems to achieve high insulin secretion and maintain beta cell viability. Here, we investigate whether co-culture of beta cells with endothelial cells could improve beta cell function within encapsulation devices.
MATERIALS AND METHODS: Mouse insulinoma MIN6 cells and human umbilical vein endothelial cells were used for creating composite aggregates on agarose microwell platform. The composite aggregates were encapsulated within flat poly(ether sulfone)/polyvinylpyrrolidone device. Their functionality was assessed by glucose-induced insulin secretion test and compared to non-encapsulated free-floating aggregates.
RESULTS: We created composite aggregates of 80-100 µm in diameter, closely mimicking pancreatic islets. Upon glucose stimulation, their insulin secretion is improved in comparison to aggregates consisting of only MIN6 cells. Moreover, the composite aggregates encapsulated within a device secrete more insulin than aggregates consisting of only MIN6 cells.
CONCLUSION: Composite aggregates of MIN6 cells with human umbilical vein endothelial cells have improved insulin secretion in comparison to MIN6 aggregates showing that the interaction of beta cell and endothelial cell is crucial for a functional encapsulation system.

Abstract
Aberrant blood vessel formation and hemorrhage may contribute to tumor progression and are potential targets in the treatment of several types of cancer. Pancreatic neuroendocrine tumors (PNETs) are highly vascularized, particularly when they are well-differentiated. However, the process of vascularization and endothelial cell detachment in PNETs is poorly understood. In the present study, 132 PNET clinical samples were examined and a special type of hemorrhagic region was observed in ~30% of the samples regardless of tumor subtype. These hemorrhagic regions were presented as blood-filled caverns with a smooth boundary and were unlined by endothelial cells. Based on the extensive endothelial cell detachment observed in the clinical samples, the formation process of these blood-filled caverns was hypothesized. Blood vessel dilation followed by detachment of endothelial cells from the surrounding tumor tissue was speculated. This was further supported using an INS-1 xenograft insulinoma model. As the formation process was distinct from the typical diffusive hemorrhage, it was named 'pseudo-hemorrhage'. Furthermore, it was demonstrated that epithelial (E-) cadherin and β-catenin were overexpressed in tumor cells surrounding these pseudo-hemorrhagic regions. Therefore, even though no statistically significant association of pseudo-hemorrhage with clinical features (metastasis or disease recurrence) was identified, the high levels of E-cadherin and β-catenin expression may suggest that a number of features of normal islet cells are retained.

Abstract
Pancreatic islets (PIs) transplantation is an alternative approach for the treatment of severe forms of type 1 diabetes (T1D). To monitor the success of transplantation, it is desirable to follow the location of engrafted PIs non-invasively. In vivo magnetic resonance imaging (MRI) of transplanted PIs is a feasible cell tracking method; however, this requires labeling with a suitable contrast agent prior to transplantation. We have tested the feasibility of cationic magnetoliposomes (MLs), compared to commercial contrast agents (Endorem and Resovist), by labeling insulinoma cells and freshly isolated rat PIs. It was possible to incorporate Magnetic Ressonance (MR)-detectable amounts of MLs in a shorter time (4 h) when compared to Endorem and Resovist. MLs did not show negative effects on the PIs' viability and functional parameters in vitro. Labeled islets were transplanted in the renal sub-capsular region of healthy mice. Hypointense contrast in MR images due to the labeled PIs was detected in vivo upon transplantation, while MR detection of PIs labeled with Endorem and Resovist was only possible after the addition of transfection agents. These findings indicate that MLs are suitable to image PIs, without affecting their function, which is promising for future longitudinal pre-clinical and clinical studies involving the assessment of PI transplantation.

Abstract
BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) are a heterogeneous group of islet cell-derived neoplasms with a propensity toward hormone production. Among PNETs, proinsulin-secreting tumors (proinsulinomas) are exceedingly rare. The objective of this study is to collect and summarize the existing literature to provide a comprehensive evaluation of this uncommon disease.
METHODS: A systematic review was performed to characterize the clinicopathologic features of proinsulinoma. Using the electronic biomedical databases PubMed, Ovid Medline, and Embase, 316 publications were screened for relevance of which 14 were selected. We also present two patients with proinsulinoma treated at Yale New Haven Hospital.
RESULTS: Of the 16 patients included in the study, the mean age was 56.8 and there was a 2:1 female predominance. The majority of patients presented with symptomatic hypoglycemia with normal or low insulin levels. Median tumor diameter was 1.2 cm and 80% were located in the body and tail of the pancreas. Following resection, most patients had normalization of hormonal levels without recurrence (75%; 12/16).
CONCLUSION: Proinsulinomas are rare pancreatic neuroendocrine tumors that have the potential to cause hypoglycemia. While insulinomas and proinsulin-secreting tumors have many physiologic parallels, these cases illustrate several key distinctions in their diagnosis and management.

Abstract
In mammalian pancreatic β cells, the IRE1α-XBP1 pathway is constitutively and highly activated under physiological conditions. To elucidate the precise role of this pathway, we constructed β cell-specific Ire1α conditional knockout (CKO) mice and established insulinoma cell lines in which Ire1α was deleted using the Cre-loxP system. Ire1α CKO mice showed the typical diabetic phenotype including impaired glycemic control and defects in insulin biosynthesis postnatally at 4-20 weeks. Ire1α deletion in pancreatic β cells in mice and insulinoma cells resulted in decreased insulin secretion, decreased insulin and proinsulin contents in cells, and decreased oxidative folding of proinsulin along with decreased expression of five protein disulfide isomerases (PDIs): PDI, PDIR, P5, ERp44, and ERp46. Reconstitution of the IRE1α-XBP1 pathway restored the proinsulin and insulin contents, insulin secretion, and expression of the five PDIs, indicating that IRE1α functions as a key regulator of the induction of catalysts for the oxidative folding of proinsulin in pancreatic β cells.

Radiosynthesis and evaluation of an 18F-labeled silicon containing exendin-4 peptide as a PET probe for imaging insulinoma.

EJNMMI Radiopharm Chem. 2018;3(1):1

Authors: Dialer LO, Jodal A, Schibli R, Ametamey SM, Béhé M

Abstract
Background: Analogues of exendin-4 have been radiolabeled for imaging the glucagon-like peptide type 1 receptors (GLP-1R) which are overexpressed in insulinoma. The aim of this research was to synthesize an 18F-labeled silicon containing exendin-4 peptide (18F-2) and to evaluate its in vitro and in vivo behavior in CHL-GLP-1 receptor positive tumor-bearing mice. 18F-labeled silicon containing exendin-4 peptide (18F-2) was prepared via one-step nucleophilic substitution of a silane precursor with 18F-fluoride in the presence of acetic acid and K222. 18F-2 was then administered to tumor-bearing mice for PET imaging and ex vivo biodistribution experiments.
Results: 18F-2 was produced in a radiochemical yield (decay corrected) of 1.5% and a molar activity of max. 16 GBq/μmol. The GLP-1R positive tumors were clearly visualized by PET imaging. Biodistribution studies showed reduced uptake of 18F-2 in the kidneys compared to radiometal labeled exendin-4 derivatives. The radiotracer showed specific tumour uptake which remained steady over 2 h.
Conclusions: This exendin-4 analogue, 18F-2, is a potential probe for imaging GLP-1R positive tumors.